Inhaled indium phosphide (InP) particulates were recently shown to cause an pleural adhesions and fibrosis in mice. These types of lesions of the pleural mesothelium are uncommon following exposure to a non-fibrous particle. An objective of initial studies was to determine if pleural lesions observed after inhalation exposure can be replicated by a single intratracheal instillation of InP. Intratracheal instillation is a much simpler procedure and allows more accurate control of dosing than does inhalation exposure. However, unlike inhalation exposure, intratracheal instillation results in a bolus dose of chemical. If intratracheal administration can be used to reproduce the pleural lesions, then this method will be used to investigate the mechanism and progression of InP induced pleural lesions. Mice received a single intratracheal instillation of InP particles (mean 0.4 micron diameter) suspended in sterile saline (PBS), at doses of 0 (PBS), 0.1, 0.5, 1 or 2 mg per mouse. Animals were euthanized 3, 7, 14, and 28 days after treatment. These time points were selected to follow the progression of effects. Endpoints included body weights, selected organ weights, bronchoalveolar lavage and pleural lavage fluid analysis (cellularity, differentials, cytokines), histopathology of lung, bronchial-associated lymph nodes and pleura, and cell proliferation in BrdU-labeled tissues. All (9/9) mice treated with 2 mg InP, 6/9 treated with 1 mg, and 1/9 treated with 0.5 mg were moribund before the end of the study. An influx of inflammatory cells was observed in all treated mice. A severe "proliferative pneumonia" was observed in lungs of the high dose group. InP was highly cytotoxic and caused a massive type II proliferative response. In addition to the severe granulomatous reaction within the lung, a significant pleural reaction was observed. It appeared that lesions occurred at areas where there is lymphatic flow (pleural lymphatics). Attempts at particle clearance led to lymphatic granuloma reactions in the pleural region, with subsequent reaction of mesothelial cells and pleural fibrosis. Because of the unexpected high toxicity, subsequent experiments will be conducted using lower intratracheal doses of InP.